DYNAMIC ” IDentifY the best therapeutic sequeNcing strAtegy in oncogene addICted NSCLC:” “A multi-arms prospective, randomized phase II study to evaluate the best sequential therapeutic strategis in patients with metastatic non-small cell lung cancer harboring targetable genomic driver alterations”

Prior treatment

• Participant has received a live vaccine within 14 days of initiating protocol therapy.
• Participant who is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment and for 180 days after the last dose of study treatment
• Male participant who is expecting to donate sperm or father children while receiving study drug or for 180 days after the last dose of study treatmen.
• Participant who received any systemic therapy for advanced disease prior of initiating the protocol therapy.
• Participant who received major surgery ≤3 weeks prior to initiating protocol therapy and/or has been recovered from any surgical effects
• Participant who received radiation therapy within 2 weeks prior to Day 1 of protocol therapy.
• Participant with diagnosis, detection, or treatment of another type of malignancy ≤2 years prior to initiating protocol therapy (except basal or squamous cell carcinoma of the skin and cervical cancer that has been definitively treated).
• Participant with a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (exceeding 10 mg of prednisone or equivalent daily) or any other form of immunosuppressive therapy within 7 days prior to initiating protocol therapy (only for study arms including PD-1/PD-L1 inhibitors).

Other illness

• Participant with a known history of human immunodeficiency virus (type 1 or 2 antibodies) (only for study arms including PD-1/PD-L1 inhibitors).
• Participant with a known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative] is detected).
• Participant with an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) (only for study arms including PD-1/PD-L1 inhibitors). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Participant with a known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis requiring steroid treatment (only for study arms including PD-1/PD-L1 inhibitors).
• Participant with known hypersensitivity to any study drugs components or excipients
• Participant with a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection

Lab values

• Participant with known, symptomatic brain or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no MRI evidence of progression for at least 4weeks after treatment is complete and within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. *For EGFR, ALK and RET positive patients who are candidates for upfront TKI therapy enrolment may be allowed following a case by case discussion with medica monitor

Other

• Participant with current participation in any interventional clinical trial.

• Patients of either sex aged ≥ 18 years
• Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X ULN (< 5 x ULN if liver metastases);
• Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula);
• Serum calcium levels, international normalised ratio (INR) and partial thromboplastin time were within normal limits
• Life expectancy of at least 3 months;
• Ability to understand study-related patient information and provision of written informed consent for participation in the study
• Histologically confirmed stage IIIB-C (unresectable and not eligible for chemoradiation) or stage IV NSCLC (AJCC Version 9).
• Treatment naïve for metastatic disease patients. Previous adjuvant treatment with both targeted therapies and checkpoint inhibitors anti PD-1/PDL-1 is allowed. (if completed at least 12 months prior to randomization, with all related adverse events have either returned to baseline or stabilized).
• Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria
• Presence of a targetable oncogenic-driver alteration (EGFR/BRAF-V600E/KRASp.G12C mutations, ALK/RET rearrangements, MET exon14 skipping alterations) identified by either tumor tissue or circulating tumor DNA analysis prior to enrollment;
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2;
• Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice a reliable method of contraception for the total study duration plus 23 weeks (i.e. 30 days plus the time required for Nivolumab to undergo five half lives) after the last dose of Nivolumab and Ipilimumab;
• Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 31 weeks (i.e. 80 days plus the time required for Nivolumab to undergo five half lives) after the last dose of Nivolumab and Ipilimumab;
• Adequate bone marrow haematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L AND platelet count ≥ 100 x 109/L AND haemoglobin ≥ 9 g/dL;